A normal parturition process is divided into three stages. Among these stages, the first and second stages are directly involved in the delivery of fetus(es). The first stage of parturition begins with the onset of rhythmic uterine contraction and ends at the complete dilation of the cervix. The complete dilation of the cervix marks the beginning of the second stage of labor which ends immediately after the birth of the neonate(s). The third stage of labor extends from the birth of the neonate(s) to the complete expulsion of the placenta.
This labor progress is driven by two types of labor forces. The primary force is produced by the involuntary contractions of uterine muscle. The secondary force is produced by the increase of intra-abdominal pressure through voluntary contractions of the abdominal muscles and diaphragm. These forces cause an increase of intrauterine pressure to provide a critical expulsion force on the fetus. In humans, said primary uterine force should generate pressures of 50-60 mm Hg, with contractions of 50-60 sec duration and occurring at a frequency of every 2-3 min. The diaphragm and abdominal muscles in the second stage should be able to double the intra-uterine pressure in response to bearing-down sensations.
Exhaustion during labor can lead to the weakening of said primary and/or secondary force, increasing labor duration and eventually resulting in dystocia (arrest of labor). Two forms of exhaustion have been identified: uterine and maternal exhaustion. Uterine exhaustion is also referred to as ‘secondary uterine inertia’, which means that the uterine muscles are fatigued and are not producing meaningful contractions. Secondary Uterine Inertia (SUI) often occurs with persistent contractions, such as during fetal dystocia. It is also very likely to occur during the delivery of the last fetuses in a large litter. Maternal exhaustion refers to the inability to sufficiently increase intrauterine pressure by contractions of the abdominal muscles and diaphragm. This inability may not only be affected by the mothers' physiological state but also by her perception of effort and exhaustion.
Serious health complications may arise in the mother from exhaustion during labor. These include retained placenta, hypocalcaemia, hypomagnesaemia, metritis, and ketosis. This can result in health complications that require medical attention during parturition (e.g., forceps or vacuum extraction or caesarian sections) or after parturition (e.g., in case of hypocalcemia).
In the fetus, serious reductions of respiration may occur as a consequence of exhaustion and numerous clinical studies have correlated a prolonged labor duration and dystocia with many undesirable outcomes, including a higher rate of infant mortality, neonatal seizures, and postpartum hemorrhage, mainly as a result of oxygen deprivation of the fetus.
For example, for some fetuses the umbilical cord is broken before time of birth, e.g. in swine this concerns approximately 20% of the fetuses. If the cord was severed just before birth, it is usually of little consequence and the neonate is born healthy. If the parturient mother is having some difficulty delivering or is tiring out, fetuses are expelled at a slower rate. For fetuses with broken cords, this delay in birthing is often fatal as interruptions in blood flow and oxygen deprivation during periods of up to five minutes appear to be tolerated by fetuses, but beyond this, it results in metabolic damage that negatively affects health and can eventually cause stillbirth (Randall, 1971).
Another factor contributing to reductions of respiration of the fetus relates to uterine contractions intensifying as offspring are being delivered. Each contraction exerts pressure on the umbilical cord and may reduce blood flow to the fetus, thus reducing the amount of oxygen reaching the unborn. Especially if the birth process tends to become delayed or interrupted due to maternal exhaustion, the unborn fetus may die from suffocation as a result of these contractions and is presented as stillbirth.
Fetuses that are born alive but which have suffered a prolonged reduction in umbilical blood flow have disturbed metabolism and respiration, including elevated levels of CO2 resulting in a decrease in blood pH. Randall (1971) showed that piglets born with an umbilical blood pH of 7.1 or lower had a low viability score. In Randall's study, 18.3% of piglets born had such low blood pH suggesting that dystocia is responsible for a large portion of neonatal mortality [Randall, G. C., The relationship of arterial blood pH and pCO2 to the viability of the newborn piglet. Can J Comp Med. 1971 April; 35(2):141-6].
For humans and large farm mammals like horses and cattle, exhaustion typically results in human intervention in the birth process. For example, oxytocin, oxytocin analogues, or oxytocin stimulants are injected to stimulate uterine contraction, or the fetus is extracted using e.g., forceps or vacuum extraction or using a caesarean section. In the UK in humans 18% of deliveries was by caesarean section, while 11.1% required instrumental deliveries (e.g., forceps and vacuum delivery). Although, most likely, these solutions are the only suitable alternatives given the conditions, mechanical interventions still can have serious implications for the health of the mother and the offspring and they may well be preventable with proper support of the mother. Furthermore, injections of oxytocin can actually be dangerous when the uterus is not properly dilated prior to administration of the intervention. Oxytocin can produce uterine spasm rather than rhythmical contractions resulting in fetal death in utero.
In the case of litter-bearing animals complications resulting from maternal and/or uterine exhaustion are even more likely to occur, whereas interventions may be less commonly available, and consequently the rate of stillbirth is much higher. For example, in swine an estimated 8% of fetuses are stillborn and 12% die shortly after birth. The incidence of low viable pigs (born weak) and stillborn pigs (intrapartum deaths) increases with birth order and with the length of parturition. It has been reported that the last pig born in a litter has a 50% chance of being stillborn, while an 11.8% perinatal mortality rate was observed in litters that farrowed in less than 6 hours, compared to 21.3% perinatal mortality rate in those litters that farrowed in more than 6 hours.
The beneficial effect of reducing farrowing intervals on stillbirth in sows was demonstrated by Rudloff and Bostedt, who studied the effect of the beta-adrenoceptor antagonist carazolol (Suacron) on farrowing in sows. In their study Rudloff and Bostedt showed that intravenous injection of 0.5 mg/50 kg bodyweight of carazolol reduced the rate of deliveries lasting more than six hours from 14.5 to 11.0%, resulting in reduced stillbirth rate from 8.3 to 7.1%, less necessity for external aid, decreased use of oxytocin, and diminishing occurrence of puerpal disorders. [Rudloff P R, Bostedt H., Effect of the beta blockader carazolol (Suacron) on parturition in sows. Tierarztl Prax. 1984; 12(4):443-449].
Preventing or reducing exhaustion may provide an interesting tool for reducing the incidence of postpartum and intrapartum morbidity or mortality, for reducing health complications in the mother resulting from exhaustive labor, and/or for reducing the need for external aid in parturient mammals. The present invention aims to provide a method of treating parturient mammals such as to realize these objectives.